Variable selection for large p small n regression models with incomplete data: Mapping QTL with epistases

<p>Abstract</p> <p>Background</p> <p>Identifying quantitative trait loci (QTL) for both additive and epistatic effects raises the statistical issue of selecting variables from a large number of candidates using a small number of observations. Missing trait and/or marker values prevent one from directly applying the classical model selection criteria such as Akaike's information criterion (AIC) and Bayesian information criterion (BIC).</p> <p>Results</p> <p>We propose a two-step Bayesian variable selection method which deals with the sparse parameter space and the small sample size issues. The regression coefficient priors are flexible enough to incorporate the characteristic of "large <it>p </it>small <it>n</it>" data. Specifically, sparseness and possible asymmetry of the significant coefficients are dealt with by developing a Gibbs sampling algorithm to stochastically search through low-dimensional subspaces for significant variables. The superior performance of the approach is demonstrated via simulation study. We also applied it to real QTL mapping datasets.</p> <p>Conclusion</p> <p>The two-step procedure coupled with Bayesian classification offers flexibility in modeling "large p small n" data, especially for the sparse and asymmetric parameter space. This approach can be extended to other settings characterized by high dimension and low sample size.</p

Neurophysiological Defects and Neuronal Gene Deregulation in Drosophila mir-124 Mutants

miR-124 is conserved in sequence and neuronal expression across the animal kingdom and is predicted to have hundreds of mRNA targets. Diverse defects in neural development and function were reported from miR-124 antisense studies in vertebrates, but a nematode knockout of mir-124 surprisingly lacked detectable phenotypes. To provide genetic insight from Drosophila, we deleted its single mir-124 locus and found that it is dispensable for gross aspects of neural specification and differentiation. On the other hand, we detected a variety of mutant phenotypes that were rescuable by a mir-124 genomic transgene, including short lifespan, increased dendrite variation, impaired larval locomotion, and aberrant synaptic release at the NMJ. These phenotypes reflect extensive requirements of miR-124 even under optimal culture conditions. Comparison of the transcriptomes of cells from wild-type and mir-124 mutant animals, purified on the basis of mir-124 promoter activity, revealed broad upregulation of direct miR-124 targets. However, in contrast to the proposed mutual exclusion model for miR-124 function, its functional targets were relatively highly expressed in miR-124–expressing cells and were not enriched in genes annotated with epidermal expression. A notable aspect of the direct miR-124 network was coordinate targeting of five positive components in the retrograde BMP signaling pathway, whose activation in neurons increases synaptic release at the NMJ, similar to mir-124 mutants. Derepression of the direct miR-124 target network also had many secondary effects, including over-activity of other post-transcriptional repressors and a net incomplete transition from a neuroblast to a neuronal gene expression signature. Altogether, these studies demonstrate complex consequences of miR-124 loss on neural gene expression and neurophysiology

Medium-size-vessel vasculitis

Medium-size-artery vasculitides do occur in childhood and manifest, in the main, as polyarteritis nodosa (PAN), cutaneous PAN and Kawasaki disease. Of these, PAN is the most serious, with high morbidity and not inconsequential mortality rates. New classification criteria for PAN have been validated that will have value in epidemiological studies and clinical trials. Renal involvement is common and recent therapeutic advances may result in improved treatment options. Cutaneous PAN is a milder disease characterised by periodic exacerbations and often associated with streptococcal infection. There is controversy as to whether this is a separate entity or part of the systemic PAN spectrum. Kawasaki disease is an acute self-limiting systemic vasculitis, the second commonest vasculitis in childhood and the commonest cause of childhood-acquired heart disease. Renal manifestations occur and include tubulointerstitial nephritis and renal failure. An infectious trigger and a genetic predisposition seem likely. Intravenous immunoglobulin (IV-Ig) and aspirin are effective therapeutically, but in resistant cases, either steroid or infliximab have a role. Greater understanding of the pathogenetic mechanisms involved in these three types of vasculitis and better long-term follow-up data will lead to improved therapy and prediction of prognosis

GWTC-2: Compact Binary Coalescences Observed by LIGO and Virgo during the First Half of the Third Observing Run

We report on gravitational-wave discoveries from compact binary coalescences detected by Advanced LIGO and Advanced Virgo in the first half of the third observing run (O3a) between 1 April 2019 15∶00 UTC and 1 October 2019 15∶00 UTC. By imposing a false-alarm-rate threshold of two per year in each of the four search pipelines that constitute our search, we present 39 candidate gravitational-wave events. At this threshold, we expect a contamination fraction of less than 10%. Of these, 26 candidate events were reported previously in near-real time through gamma-ray coordinates network notices and circulars; 13 are reported here for the first time. The catalog contains events whose sources are black hole binary mergers up to a redshift of approximately 0.8, as well as events whose components cannot be unambiguously identified as black holes or neutron stars. For the latter group, we are unable to determine the nature based on estimates of the component masses and spins from gravitational-wave data alone. The range of candidate event masses which are unambiguously identified as binary black holes (both objects ≥ 3 M⊙) is increased compared to GWTC-1, with total masses from approximately 14 M⊙ for GW190924_021846 to approximately 150 M⊙ for GW190521. For the first time, this catalog includes binary systems with significantly asymmetric mass ratios, which had not been observed in data taken before April 2019. We also find that 11 of the 39 events detected since April 2019 have positive effective inspiral spins under our default prior (at 90% credibility), while none exhibit negative effective inspiral spin. Given the increased sensitivity of Advanced LIGO and Advanced Virgo, the detection of 39 candidate events in approximately 26 weeks of data (approximately 1.5 per week) is consistent with GWTC-1

The effect of dietary restriction on reproduction: a meta-analytic perspective

Background: Dietary restriction (DR), a reduction in the amount of food or particular nutrients eaten, is the most consistent environmental manipulation to extend lifespan and protect against age related diseases. Current evolutionary theory explains this effect as a shift in the resolution of the trade-off between lifespan and reproduction. However, recent studies have questioned the role of reproduction in mediating the effect of DR on longevity and no study has quantitatively investigated the effect of DR on reproduction across species. Results: Here we report a comprehensive comparative meta-analysis of the effect of DR on reproduction. In general, DR reduced reproduction across taxa, but several factors moderated this effect. The effect of DR on reproduction was greater in well-studied model species (yeast, nematode worms, fruit flies and rodents) than non-model species. This mirrors recent results for longevity and, for reproduction, seems to result from a faster rate of decline with decreasing resources in model species. Our results also suggested that not all reproductive traits are affected equally by DR. High and moderate cost reproductive traits suffered a significant reduction with DR, but low cost traits, such as ejaculate production, did not. Although the effect of DR on reproduction was stronger in females than males, this sex difference reduced to near zero when accounting for other co-factors such as the costliness of the reproductive trait. Thus, sex differences in the effect of DR on longevity may be due to a failure to expose males to as complete a range of the costs of reproduction as females. Conclusions: We suggest that to better understand the generality of the effect of DR, future studies should attempt to address the cause of the apparent model species bias and ensure that individuals are exposed to as many of the costs of reproduction as possible. Furthermore, our meta-analytic approach reveals a general shortage of DR studies that record reproduction, particularly in males, as well as a lack of direct side-by-side comparisons of the effect of DR on males and females

The Event Horizon General Relativistic Magnetohydrodynamic Code Comparison Project

Recent developments in compact object astrophysics, especially the discovery of merging neutron stars by LIGO, the imaging of the black hole in M87 by the Event Horizon Telescope, and high- precision astrometry of the Galactic Center at close to the event horizon scale by the GRAVITY experiment motivate the development of numerical source models that solve the equations of general relativistic magnetohydrodynamics (GRMHD). Here we compare GRMHD solutions for the evolution of a magnetized accretion flow where turbulence is promoted by the magnetorotational instability from a set of nine GRMHD codes: Athena++, BHAC, Cosmos++, ECHO, H-AMR, iharm3D, HARM-Noble, IllinoisGRMHD, and KORAL. Agreement among the codes improves as resolution increases, as measured by a consistently applied, specially developed set of code performance metrics. We conclude that the community of GRMHD codes is mature, capable, and consistent on these test problems

Dyssynchronization reduces dynamic obstruction without affecting systolic function in patients with hypertrophic obstructive cardiomyopathy: a pilot study

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